The present invention relates to a process for heterogeneously, asymmetrically hydrogenating racemic xcex1-ketoethers using a platinum catalyst in the presence of a chiral aromatic nitrogen base and optionally a strong base to give enantiomeric xcex1-hydroxyethers.
Optically active xcex1-hydroxyethers are valuable intermediates for preparing tricyclic xcex2-lactam antibiotics (Matsumoto, T. et al. THL 40 (1999) 5043) and natural compounds (Murata, K., et al., Org. Lett. 1 (1999) 1119), active pharmaceutical ingredients and pesticides. As early as 1979, Y. Orito et al. in Nippon Kagaku Kuishi 1979(8), pages 1118-1120 disclose that optically active xcex1-hydroxycarboxylic esters are obtainable in good optical yields by hydrogenating xcex1-ketocarboxylic esters using platinum metal catalysts in the presence of a cinchona alkaloid. The influence of solvents and other reaction conditions in this hydrogenation is described by H. U. Blaser et al. in J. of Mol. Cat. 68 (1991), pages 215 to 222. Further investigations have shown (see H. U. Blaser et al. in Catalysis Today 37 (1997), pages 441 to 461) that the catalytic hydrogenation system has a high substrate specificity. Even the use of xcex1-diketones instead of the xcex1-ketocarboxylic esters (optical yield ee up to 95%) leads to considerably reduced optical yields (ee only 38 to 50%, see also W. A. H. Vermeer et al. in J. Chem. Soc., Chem. Comm., 1993, pages 1053 to 1054 and M. Studer et al. in J. Chem. Soc., Chem. Comm., 1998, page 1053). When an unsubstituted methyl xcex1-ketoether such as methoxyacetone is used, the effect is even more pronounced and an optical yield of only about 12% ee is obtained (H. U. Blaser et al. in Heterogeneous Catalysis and Fine Chemicals, Elsevier Science Publishers B. V., Amsterdam, 1998, pages 153 to 163). WO 01/00545 discloses that, in contrast, xcex1-ketoacetals in this hydrogenation deliver excellent chemical and optical yields.
The targeted preparation of substituted enantiomeric xcex1-hydroxyethers from prochiral xcex1-ketoethers by heterogeneous hydrogenation using platinum catalysts in the presence of a chiral nitrogen base has hitherto not been described. It has now been found that, surprisingly, this type of hydrogenation selectively hydrogenates only one diastereomer to virtual completion and accordingly very high chemical and optical yields are achievable, especially because the reactants and adducts are easily separable owing to their differing physical properties.
It is known that xcex1-ketoethers can be racemized using soluble strong bases. Although soluble bases accelerate the reaction, they lead to a completely racemized product. It was found that, surprisingly, the yield of the desired diastereomer could be greatly increased when a strong heterogeneous base was added to the reaction mixture. During the hydrogenation, the undesired diastereomer is racemized and the desired diastereomer is formed and hydrogenated. In this manner, the chemical yield can be greatly increased to over 90% and more.
The invention accordingly provides a process for heterogeneously and enantioselectively hydrogenating organic xcex1-keto compounds using a platinum catalyst in the presence of a soluble or immobilized chiral aromatic nitrogen base having at least one basic nitrogen atom neighbouring at least one stereogenic carbon atom, which is characterized in that racemic xcex1-ketoethers are hydrogenated to optically active xcex1-hydroxyethers.
Neighbouring stereogenic carbon atoms means that the nitrogen atom is not bonded to the stereogenic carbon atom, but instead that the basic nitrogen atom is in the xcex2- and more preferably in the xcex1-position to at least one stereogenic carbon atom.
The racemic xcex1-ketoethers may be saturated or unsaturated, open-chain or cyclic compounds which preferably have 5 to 50, more preferably 5 to 30, carbon atoms and are unsubstituted or substituted by one or more radicals which are stable under the hydrogenation conditions. The carbon chain may be interrupted by heteroatoms, preferably from the group of xe2x80x94Oxe2x80x94, xe2x95x90Nxe2x80x94 and xe2x80x94NRxe2x80x2xe2x80x94 and/or xe2x80x94C(O)xe2x80x94, xe2x80x94C(NRxe2x80x2)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NRxe2x80x2xe2x80x94 where Rxe2x80x2 is H, C1-C8-alkyl, C5- or C6-cycloalkyl or C6-C10-aryl, for example phenyl or naphthyl, or phenylmethyl or phenylethyl.
Examples of useful inert substituents include alkyl, alkenyl, alkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, aryl, aryloxy, aralkyl, aralkoxy, halogen, xe2x80x94OH, xe2x80x94OR4, xe2x80x94OC(O)R4, xe2x80x94NHxe2x80x94C(O)xe2x80x94R4, xe2x80x94NR4xe2x80x94C(O)xe2x80x94R4, xe2x80x94CO2R4, xe2x80x94CO2xe2x80x94NH2, xe2x80x94CO2xe2x80x94NHR4, and xe2x80x94CO2xe2x80x94NR4R5 where R4 and R5 are each independently C1-C4-alkyl, cyclohexyl, cyclohexylmethyl, phenyl or benzyl.
The xcex1-ketoethers are preferably of the formula I, 
where R1, R2 and R3 are each independently a monovalent, saturated or unsaturated aliphatic radical having 1 to 12 carbon atoms, a saturated or unsaturated cycloaliphatic radical having 3 to 8 carbon atoms, a saturated or unsaturated heterocycloaliphatic radical having 3 to 8 ring members and one or two heteroatoms from the group of O, N and NRxe2x80x2, a saturated or unsaturated cycloaliphatic-aliphatic radical having 4 to 12 carbon atoms, a saturated or unsaturated heterocycloaliphatic-aliphatic radical having 3 to 12 carbon atoms and one or two heteroatoms from the group of O, N and NRxe2x80x2, an aromatic radical having 6 to 10 carbon atoms, a heteroaromatic radical having 4 to 9 carbon atoms and one or two heteroatoms from the group of O and N, an aromatic-aliphatic radical having 7 to 12 carbon atoms or a heteroaromatic-aliphatic radical having 5 to 11 carbon atoms and one or two heteroatoms from the group of O and N where Rxe2x80x2 is H, C1-C8-alkyl, preferably C1-C4-alkyl, C5- or C6-cycloalkyl or C6-C10-aryl, for example phenyl or naphthyl, phenyl or phenylethyl, R1 and R2 together or R1 and R3 together form a direct bond, C1-C6-alkylene, C3-C8-cycloalkyl-1,2-ene, C3-C8-cycloalkyl-C1-C4-alkylene, C2-C7-heterocycloalkyl-1,2-ene or C2-C7-heterocycloalkyl-C1-C4-alkylene having one or two heteroatoms from the group of O and N, C6-C10-aryl-C1-C4-alkylene, C5-C9-heteroaryl-C1-C4-alkylene having one or two heteroatoms from the group of O and N; or C2-C10-alkylene, C3-C8-cycloalkylene or C2-C7-heterocycloalkylene having one or two heteroatoms from the group of O and N, each of which is fused to C3-C8-cycloalkyl-1,2-ene, C2-C7-heterocycloalkyl-1,2-ene having one or two heteroatoms from the group of O and N, C6-C10-aryl-1,2-ene or C5-C9-heteroaryl-1,2-ene having one or two heteroatoms from the group of O and N, and R3 and R2 respectively are each as defined above,
R2 and R3 together are C1-C6-alkylene, C1-C8-alkylidene, C3-C8-cycloalkylidene, benzylidene, C3-C8-cycloalkyl-1,2-ene, C3-C8-cycloalkyl-C1-C4-alkylene, C2-C7-heterocycloalkyl-1,2-ene or C2-C7-heterocycloalkyl-C1-C4-alkylene having one or two heteroatoms from the group of O and N, C6-C10-aryl-C1-C4-alkylene, C5-C9-heteroaryl-C1-C4-alkylene having one or two heteroatoms from the group of O and N; or C2-C10-alkylene, C3-C8-cycloalkylene or C2-C7-heterocycloalkylene having one or two heteroatoms from the group of O and N, each of which is fused to C3-C8-cycloalkyl-1,2-ene, C2-C7-heterocycloalkyl-1,2-ene having one or two heteroatoms from the group of O and N, C6-C10-aryl-1,2-ene or C5-C9-heteroaryl-1,2-ene having one or two heteroatoms from the group of O and N, and R1 is as defined above, and R1, R2 and R3 are each unsubstituted or substituted by one or more, identical or different radicals selected from the group of C1-C4-alkyl, C2-C4-alkenyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxymethyl or -ethyl, C1-C4-haloalkoxy, cyclohexyl, cyclohexyloxy, cyclohexylmethyl, cyclohexylmethyloxy, phenyl, phenyloxy, benzyl, benzyloxy, phenylethyl, phenylethyloxy, halogen, xe2x80x94OH, xe2x80x94OR4, xe2x80x94OC(O)R4, xe2x80x94NH2, xe2x80x94NHR4, xe2x80x94NR4R5, xe2x80x94NHxe2x80x94C(O)xe2x80x94R4, xe2x80x94NR4xe2x80x94C(O)xe2x80x94R4, xe2x80x94CO2R4, xe2x80x94CO2xe2x80x94NH2, xe2x80x94CO2xe2x80x94NHR4, xe2x80x94CO2xe2x80x94NR4R5, where R4 and R5 are each independently C1-C4-alkyl, cyclohexyl, cyclohexylmethyl, phenyl or benzyl.
The heterocyclic radicals are bonded via a ring carbon atom to the oxygen atom or the carbon atom of the carbonyl group in formula I.
Preferred substituents include methyl, ethyl, n- and i-propyl, n- and t-butyl, vinyl, allyl, methyloxy, ethyloxy, n- and i-propyloxy, n- and t-butyloxy, trifluoromethyl, trichloromethyl, xcex2-hydroxyethyl, methoxy- or ethoxymethyl or -ethyl, trifluoromethoxy, cyclohexyl, cyclohexyloxy, cyclohexylmethyl, cyclohexylmethyloxy, phenyl, phenyloxy, benzyl, benzyloxy, phenylethyloxy, phenylethyl, halogen, xe2x80x94OH, xe2x80x94OR4, xe2x80x94OC(O)R4, xe2x80x94NH2, xe2x80x94NHR4, xe2x80x94NR4R5, xe2x80x94NHxe2x80x94C(O)xe2x80x94R4, xe2x80x94NR4xe2x80x94C(O)xe2x80x94R4, xe2x80x94CO2R4, xe2x80x94CO2xe2x80x94NH2, xe2x80x94CO2xe2x80x94NHR4, xe2x80x94CO2xe2x80x94NR4R5 where R4 and R5 are each independently C1-C4-alkyl, cyclohexyl, cyclohexylmethyl, phenyl or benzyl.
The aliphatic radical is preferably alkyl which may be linear or branched and preferably contains 1 to 8, more preferably 1 to 4, carbon atoms, or preferably alkenyl or alkynyl which may be linear or branched and preferably contains 2 to 8, more preferably 2 to 4, carbon atoms. When R2 and R3 are alkenyl or alkynyl, the unsaturated bond is preferably in the xcex2-position to the oxygen atom. Examples include methyl, ethyl, n- and i-propyl. n-, i- and t-butyl, pentyl, i-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl, vinyl, allyl, ethynyl and propargyl. A preferred group of aliphatic radicals consists of methyl, ethyl, n- and i-propyl, n-, i- and t-butyl.
The cycloaliphatic radical is preferably cycloalkyl or cycloalkenyl having preferably from 3 to 8, more preferably 5 or 6, ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and also cyclopentenyl, cyclohexenyl and cyclohexadienyl. Particular preference is given to cyclopentyl and cyclohexyl.
The heterocycloaliphatic radical is preferably heterocycloalkyl or heterocycloalkenyl preferably having 3 to 6 carbon atoms, 4 to 7 ring members and heteroatoms selected from the group of xe2x80x94Oxe2x80x94 and xe2x80x94NRxe2x80x2xe2x80x94 where Rxe2x80x2 is H, C1-C8-alkyl, preferably C1-C4-alkyl, C5- or C6-cycloalkyl or C6-C10-aryl, for example phenyl or naphthyl, phenyl or phenylethyl. Examples include pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, dihydrofuranyl and piperazinyl.
The cycloaliphatic-aliphatic radical is preferably cycloalkyl-alkyl or -alkenyl preferably having 3 to 8, more preferably 5 or 6, ring carbon atoms, and preferably 1 to 4 or 2-4, more preferably 1 or 2, or 2 or 3, carbon atoms in the alkyl group or alkenyl group respectively. Examples include cyclopentyl- or cyclohexylmethyl or -ethyl and cyclopentyl- or cyclohexylethenyl.
The heterocycloaliphatic-aliphatic radical is preferably heterocycloalkyl-alkyl or -alkenyl preferably having 3 to 6 carbon atoms, 4 to 7 ring members and heteroatoms selected from the group of xe2x80x94Oxe2x80x94 and xe2x80x94NRxe2x80x2xe2x80x94 where Rxe2x80x2 is H, C1-C8-alkyl, preferably C1-C4-alkyl, C5- or C6-cycloalkyl or C6-C10-aryl, for example phenyl or naphthyl, phenyl or phenylethyl, and preferably 1 to 4, more preferably 1 or 2, carbon atoms in the alkyl group or 2 to 4, and more preferably 2 or 3, carbon atoms in the alkenyl group. Examples include pyrrolidinylmethyl or -ethyl or -ethenyl, pyrrolinylmethyl or -ethyl or -ethenyl, tetrahydrofuranylmethyl or -ethyl or -ethenyl, dihydrofuranylmethyl or -ethyl or -ethenyl, and piperazinylmethyl or -ethyl or -ethenyl.
The aromatic radicals are particularly naphthyl and in particular phenyl.
The aromatic-aliphatic radicals are preferably phenyl- or naphthyl-C1-C4-alkyl or xe2x80x94C2-C4-alkenyl. Examples include benzyl, naphthylmethyl, xcex2-phenylethyl and xcex2-phenylethenyl.
The heteroaromatic radicals are preferably 5- or 6-membered, optionally fused, ring systems. Examples include pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, oxazolyl, imidazolyl, benzofuranyl, indolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl.
The heteroaromatic-aliphatic radicals are preferably 5- or 6-membered, optionally fused, ring systems which are bonded via one of their carbon atoms to the free bond of an alkyl group which preferably has 1 to 4, more preferably 1 or 2, carbon atoms, or of an alkenyl group which preferably has 2 to 4, more preferably 2 or 3, carbon atoms. Examples include pyridinylmethyl or -ethyl or -ethenyl, pyrimidinylmethyl or -ethyl or -ethenyl, pyrrolylmethyl or -ethyl or -ethenyl, furanylmethyl or -ethyl or -ethenyl, imidazolylmethyl or -ethyl or -ethenyl, indolylmethyl or -ethyl or -ethenyl.
More preferred compounds of the formula I include those where
R1, R2 and R3 are each independently linear or branched C1-C8-alkyl, C4-C7-cycloalkyl or C4-C6-heterocycloalkyl having heteroatoms from the group of O and N, C6-C10-aryl or C4-C9-heteroaryl having heteroatoms from the group of O and N, C4-C7-cycloalkyl-C1-C4-alkyl or C3-C6-heterocycloalkyl-C1-C4-alkyl having heteroatoms from the group of O and N, C6-C10-aryl-C1-C4-alkyl or C4-C9-heteroaryl-C1-C4-alkyl having heteroatoms from the group of O and N,
R1 and R2 together or R1 and R3 together are each C1-C4-alkylene or C4-C7-1,2-cycloalkylene, or C2-C4-alkylene or C4-C7-cycloalkylene fused to 1,2-phenylene, and R3 or R2 respectively are each as defined above,
R2 and R3 together are C1-C4-alkylene, C1-C4-alkylidene, C4-C7-1,2-cycloalkylene, C4-C7-cycloalkylidene, benzylidene, 1,2-phenylene, 1,2-pyridinylene or 1,2-naphthylene, or C3-C4-alkylene or C4-C7-cycloalkylene fused to 1,2-cycloalkylene or to 1,2-phenylene, and R1 is as defined above,
where R1, R2 and R3 are each unsubstituted or substituted by one or more, identical or different radicals selected from the group of C1-C4-alkyl, C1-C4-alkoxy, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxymethyl or -ethyl, C1-C4-haloalkoxy, cyclohexyl, cyclohexyloxy, cyclohexylmethyl, cyclohexylmethyloxy, phenyl, phenyloxy, benzyl, benzyloxy, phenylethyl, phenylethyloxy, halogen, xe2x80x94OH, xe2x80x94OR4, xe2x80x94OC(O)R4, xe2x80x94NH2, xe2x80x94NHR4, xe2x80x94NR4R5, xe2x80x94NHxe2x80x94C(O)xe2x80x94R4, xe2x80x94NR4xe2x80x94C(O)xe2x80x94R4, xe2x80x94CO2R4, xe2x80x94CO2xe2x80x94NH2, xe2x80x94CO2-NHR4 and xe2x80x94CO2xe2x80x94NR4R5 where R4 and R5 are each independently C1-C4-alkyl, cyclohexyl, phenyl or benzyl.
A preferred subgroup of the compounds of the formula I includes those where
R1, R2 and R3 are each independently linear or branched C1-C4-alkyl, C2-C4-alkenyl, C5-C6-cycloalkyl, phenyl, phenylethenyl, C5-C6-cycloalkyl-C1-C2-alkyl or C6-C10-aryl-C1-C2-alkyl,
R1 and R2 together or R1 and R3 together are C1-C3-alkylene or C5-C6-1,2-cycloalkylene, R2 and R3 together are C2-C4-alkylene, C1-C4-alkylidene, C5-C6-1,2-cycloalkylene, C5-C6-cycloalkylidene, benzylidene or 1,2-phenylene,
where R1, R2 and R3 are each unsubstituted or substituted as defined above.
A particularly preferred subgroup of the compounds of the formula I includes those where
R1 is C1-C4-alkyl, C2-C4-alkenyl, cyclohexyl, phenyl, benzyl, phenylethyl or phenylethenyl,
R2 and R3 are each independently linear or branched C1-C4-alkyl, cyclohexyl, phenyl, benzyl or phenylethyl,
R1 and R2 together or R1 and R3 together are each C2-C3-alkylene or 1,2-cyclohexylene, R2 and R3 together are C2-C3-alkylene, C1-C4-alkylidene, 1,2-cyclohexylene, cyclohexylidene, benzylidene or 1,2-phenylene,
where R1, R2 and R3 are each unsubstituted or substituted by methyl, ethyl, n- and i-propyl, n- and t-butyl, vinyl, allyl, methyloxy, ethyloxy, n- and i-propyloxy, n- and t-butyloxy, trifluoromethyl, trichloromethyl, xcex2-hydroxyethyl, methoxy- or ethoxymethyl or -ethyl, trifluoromethoxy, cyclohexyl, cyclohexyloxy, cyclohexylmethyl, cyclohexylmethyloxy, phenyl, phenyloxy, benzyl, benzyloxy, phenylethyloxy, phenylethyl, halogen, xe2x80x94OH, xe2x80x94OR4, xe2x80x94OC(O)R4, xe2x80x94NH2, xe2x80x94NHR4, xe2x80x94NR4R5, xe2x80x94NHxe2x80x94C(O)xe2x80x94R4, xe2x80x94NR4xe2x80x94C(O)xe2x80x94R4, xe2x80x94CO2R4, xe2x80x94CO2xe2x80x94NH2, xe2x80x94CO2xe2x80x94NHR4 or xe2x80x94CO2xe2x80x94NR4R5 where R4 and R5 are each independently C1-C4-alkyl, cyclohexyl, cyclohexylmethyl, phenyl or benzyl.
xcex1-Ketoethers are known or may be prepared in a conventional manner by the literature processes.
The xcex1-ketoethers, in particular those of the formula I, are hydrogenated to chiral secondary alcohols of the formula II 
where R1, R2 and R3 are each as defined above and the symbol * represents predominantly the R- or S-form of one of the stereoisomers.
Platininum catalysts are known, extensively described and commercially available. Platinum can easily be used in metallic form, for example as powder, or else, preferably, as platinum metal applied to a finely divided support. Examples of useful supports include carbon, metal oxides, for example SiO2, TiO2 or Al2O3, metal salts, and natural or synthetic silicates. The catalyst may also be a platinum colloid. The quantity of platinum metal on the support may be, for example 1 to 10, preferably 3 to 8, % by weight, based on the support. Before use, the catalysts may be activated by treatment with hydrogen at elevated temperature or using ultrasound.
Chiral and aromatic nitrogen bases as modifiers for platinum-catalyzed enantioselective hydrogenation are likewise known and described, for example, by H. U. Blaser et al. in Catalysis Today 37 (1997), pages 441 to 463. Particularly useful nitrogen bases have an aromatic or heteroaromatic, mono- or polycyclic, ring system, preferably a mono- to tricyclic ring, optionally in combination with fused-on cycloaliphatic or heterocycloaliphatic rings, and the basic nitrogen atom or atoms are bonded in the xcex1- and preferably in the xcex2-position to a chiral carbon atom and the nitrogen atoms are ring members of a chiral N-heterocyclo-aliphatic ring or are bonded to a ring via a chiral C1- or C2-group.
Preference is given to cinchona alkaloids and derivatives thereof. They may, for example, be of the formula III 
where R is H, C1-C4-alkyl, C1-C4-alkyl-C(O)xe2x80x94, C1-C4-hydroxyalkyl-C(O)xe2x80x94, phenyl-C(O)xe2x80x94 or benzyl-C(O)xe2x80x94, R6 is H, C1-C4-alkyl, C1-C4-hydroxyalkyl or C2-C4-alkenyl, and the symbol * represents the R- or S-form of the stereocentres. Preference is given to cinchona alkaloids where R6 in the formula III is H, methyl, ethyl or vinyl, and R is H, methyl, ethyl or acetyl.
The choice of the nitrogen base predetermines which of the enantiomeric xcex1-hydroxyethers is formed predominantly.
The catalyst (for example 5% of Pt/Al2O3) may be used, for example in a quantity of 0.01 to 10, preferably 0.05 to 50 and more preferably 0.1 to 10, % by weight, based on the xcex1-ketoether used, although quantities of 0.1 to 5% by weight, or 0.1 to 1% by weight generally suffice.
The nitrogen base is added, for example, in a quantity of from 0.1 to 1 000, preferably 1 to 500 and more preferably 10 to 200, % by weight, based on the platinum metal catalyst used. The nitrogen base may be added together with the platinum metal catalyst into the reaction vessel, or the platinum catalyst may be impregnated with the nitrogen base, for example a cinchona alkaloid, in a preceding step.
Preference is given to carrying out the hydrogenation under a hydrogen pressure of up to 200 bar, more preferably up to 150 bar and particularly preferably 10 to 100 bar.
The reaction temperature may be, for example xe2x88x9250 to 100xc2x0 C., more preferably 0 to 50xc2x0 C. and particularly preferably 0 to 35xc2x0 C.
The reaction may be carried out without or in an inert solvent. Examples of useful solvents include aliphatic, cycloaliphatic and aromatic hydrocarbons (pentane, hexane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene or xylene), ethers (diethyl ether, dibutyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran or dioxane), alcohols (methanol, ethanol, propanol, butanol, ethylene glycol, diethylene glycol, ethylene glycol monomethyl or monoethyl ether or diethylene glycol monomethyl or monoethyl ether), ketones (acetone or methyl isobutyl ketone), carboxylic esters and lactones (ethyl acetate or methyl acetate, valerolactone), N-substituted carboxamides and lactams (dimethylformamide or N-methylpyrrolidone) and carboxylic acids (acetic acid, propionic acid or butyric acid). The optical yield may be influenced by the choice of solvent.
It has proven particularly advantageous to carry out the process according to the invention in the presence of at least one strong base in solid form which is insoluble in the reaction mixture. The base is used advantageously in finely divided form (powder). The term insoluble also includes bases which can be swollen in the reaction system. These bases may in particular be those strong bases which are able to deprotonate the chiral CH group of the xcex1-ketoethers in order to racemize the non-hydrogenatable diastereomers. Preference is given to bases having OHxe2x88x92 groups, for example alkali metal hydroxides and in particular optionally crosslinked homo- or copolymers having ammonium hydroxide groups or inorganic supports modified with ammonium hydroxide groups. Among the polymeric ammonium hydroxides, preference is given to those based on optionally crosslinked polyaminostyrenes. These strong bases are familiar as anion exchangers and are commercially available. Examples include the amberlites (Amberlite(copyright) IRA-900) from Fluka AG, a crosslinked copolymer or styreneammonium chloride and divinylbenzene which is activated using aqueous alkali before use. Inorganic supports, for example glass, metal oxides, silica gel or silicates, may be modified, for example, using aminoalkyltrialkoxysilanes and then converted using ammonia salts such as halides by treatment with bases to the ammonium hydroxide form. The quantity of the solid base may be, for example from 1 to 100, preferably from 10 to 90 and more preferably from 20 to 80, % by weight, based on the xcex1-ketoether.
The process according to the invention may be carried out in such a manner that, for example, the catalyst is initially charged with the chiral nitrogen base into an autoclave, optionally with a solvent, then the xcex1-ketoether is added, air is expelled using an inert gas, for example noble gases or hydrogen, hydrogen is injected, and the reaction is started, optionally with stirring or shaking, and hydrogenation is effected until such time as no more hydrogen takeup is observed. The xcex1-hydroxyether formed may be isolated and purified by customary methods, for example distillation, crystallization and chromatographic methods. The process according to the invention provides the desired xcex1-hydroxyethers in high chemical and optical yields, and high catalyst activity is additionally observed so that even the use of small catalyst quantities provides an economical process. Furthermore, insoluble strong bases are successfully used for the first time in a dynamic, kinetic optical resolution in a heterogeneous reaction system in order to achieve higher yields of the desired diastereomers.